The present invention relates to methods for modifying metallotexaphyrins to provide metallotexaphyrin derivatives (MTDs) having a wide range of physicochemical properties. In particular, the methods involve modifying the apical ligands associated with the central metal component of metallotexaphyrins. The invention also relates to the novel MTDs prepared by these methods, and their uses, and pharmaceutical compositions containing such compounds.
Porphyrins, the so-called xe2x80x9cexpanded porphyrinsxe2x80x9d, and related polypyrrole structures are members of a class of macrocycles capable of forming stable complexes with metals. The metal is constrained (as its cation) within a central binding cavity of the macrocycle (the xe2x80x9ccorexe2x80x9d). The anions associated with the metal cation are found above and below the core; and are called apical ligands. Examples of this class of macrocycles are porphyrins, porphyrin isomers, porphyrin-like macrocycles, benzoporphyrins, texaphyrins, alaskaphyrins, sapphyrins, rubyrins, porphycenes, chlorins, benzochlorins, and purpurins.
One preferred class of macrocycles is the texaphyrins. Texaphyrins are aromatic pentadentate macrocyclic compounds that have the ability to integrate metals within their core to form complexes known as xe2x80x9cmetallotexaphyrinsxe2x80x9d. Texaphyrins and metallotexaphyrins have been described as being useful as MRI contrast agents, fluorescent imaging agents for cancer, plaque, and retinal diseases, as radiosensitizers and as chemosensitizers in both oncology and atherosclerosis, and as photosensitizers in photodynamic therapy in oncology, atherosclerosis, and ophthamology. They have also been described as having the ability to hydrolytically cleave phosphate esters such as RNA, and to photolytically cleave RNA and DNA. Texaphyrins are aromatic benzannulene compounds containing both 18xcfx80- and 227xcfx80-electron delocalization pathways. Texaphyrin molecules absorb light strongly in the tissue-transparent 700-900 nm range, and they exhibit selective uptake (or biolocalization) in certain tissues, particularly regions such as liver, atheroma or tumor tissue, and neovascularized regions. Such selectivity can be detected by magnetic resonance imaging (for example with paramagnetic metal complexes) and by fluorescence.
Accordingly, advantage may be taken of this property to provide a means for selectively treating tumors, plaque caused by atherosclerosis, retinal diseases, and the like, as disclosed in the publications incorporated by reference below in the detailed description of the invention. Notwithstanding these properties, it has remained desired to provide new MTDs having a range of physicochemical properties, such, as improved solubility and/or lipophilicity, lower toxicity, and improved stability, but still retaining the basic attribute of selective localization.
One method of accomplishing these goals would be to change the properties of existing metallotexaphyrins by modifying the functional groups covalently attached to the macrocycle, and/or by changing the core metal. However, preparations of such MTDs require complicated syntheses, since each compound is necessarily made by a different synthetic route, and/or is derived from different starting materials. Accordingly, there remains a need for a convenient method for preparing a library of texaphyrin derivatives, which vary in their physicochemical properties, and can be synthesized easily and efficiently in high yield. The present invention provides such a method by modifying the apical ligands associated with the metal component of existing metallotexaphyrins to provide a library of MTDs having a wide range of physicochemical properties.
It is an object of this invention to provide novel metallotexaphyrin derivatives (MTDs). Accordingly, in a first aspect, the invention relates to compounds having the Formula I: 
wherein:
M is a metal cation;
AL is an apical ligand;
with the proviso that AL is not derived from acetic acid, nitric acid, or hydrochloric acid; n is an integer of 1-5;
R1, R2, R3, R4, R5, R6, R8, and R9 are independently chosen from the group consisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy, saccharide, optionally substituted amino, carboxyl, optionally substituted carboxyalkyl, optionally substituted carboxyamide, optionally substituted carboxyamidealkyl, optionally substituted heterocycle, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkylalkyl; and a group xe2x80x94Xxe2x80x94Y, in which X is a covalent bond or a linker and Y is a catalytic group, a chemotherapeutic agent, or a site-directing molecule, and;
R5, R10, R11, and R12 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted carboxyalkyl, or optionally substituted carboxyamidealkyl; with the proviso that: halogen is other than iodide and haloalkyl is other than iodoalkyl.
Substituents R1-R12 are further described in U.S. patents, PCT publications and allowed and pending patent applications, incorporated by reference in the Detailed Description.
M can be monovalent, divalent, trivalent, or tetravalent. Examples of monovalent metal cations are tellurium and technetium; an example of an appropriate tetravalent metal is thorium. Preferred are divalent and trivalent metals. Preferred divalent metal cations are Ca(II), Mn(II), Co(II), Ni(II), Zn(II), Cd(II), Hg(III), Fe(II), Sm(II), or U(II). Preferred trivalent metal cations are Mn(III), Co(III), Ni(III), Fe(III), Ho(III), Ce(III), Y(III), In(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Er(III), Tm(III), Yb(III), Lu(III), La(III), or U(III). More preferred trivalent metal cations are Lu(III) or Gd(III). In some embodiments, in particular for use in neutron capture therapy, the metal can be present as a pure isotope of the metal, or be enriched in one or more of its isotopes. For example, gadolinium may be present as its 155Gd or 157Gd isotope, or xe2x80x9cnaturalxe2x80x9d gadolinium may be optionally enriched in the isotopes 155Gd and/or 157Gd. Similarly, cadmium may be present as the cadmium isotope 113Cd, or xe2x80x9cnaturalxe2x80x9d cadmium enriched in 113Cd; europium may be present as the europium isotope 115Eu, or xe2x80x9cnaturalxe2x80x9d europium enriched in 151Eu; mercury may be present as the mercury isotope 199Hg, or xe2x80x9cnaturalxe2x80x9d mercury enriched in 199Hg; and samarium may be present as the samarium isotope 149Sm. or xe2x80x9cnaturalxe2x80x9d samarium enriched in 149Sm. Particularly preferred for neutron capture therapy is the 157Gd isotope of gadolinium, or xe2x80x9cnaturalxe2x80x9d gadolinium enriched in the isotope 157Gd.
M or one of groups R1 to R12 can be radioactive, and are as described in the U.S. patents, PCT publications, and allowed and pending patent applications disclosed and incorporated by reference below.
Preferred apical ligands are formed, for example, from carboxylates of sugar derivatives, such as gluconic acid or glucoronic acid, cholesterol derivatives such as cholic acid and deoxycholic acid, polyethylene glycol (PEG) acids, or carboxylic acid derivatives, such as formic acid, propionic acid, butyric acid, pentanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, 3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic 2,5-dioxoheptanoic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid. Other preferred acids for forming apical ligands include methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, organophosphates, such as methylphosphonic acid and phenylphosphonic acid, phosphoric acid and the like.
A second aspect of the present invention relates to a preferred process for synthesizing MTDs of Formula I, comprising the steps of contacting the desired apical ligand with an quartenary amine resin (e.g., Ambersep 900(OH), Amberlite IRA904), contacting the apical ligand/amino acid resin complex thus produced with a metallotexaphyrin, preferably a metallotexaphyrin acetate, and isolating the MTD of Formula I having the desired novel apical ligand.
A third aspect of the present invention relates to an alternative process for synthesizing MTDs of Formula I, comprising the steps of contacting a metallotexaphyrin, preferably as an acetate, with a large excess of the chosen apical ligand, optionally heating the mixture, and isolating the MTD of Formula I containing the novel apical ligand.
A fourth aspect of the present invention relates to a process for synthesizing MTDs having a mixture of apical ligands, comprising the steps of contacting a metallotexaphyrin, preferably a metallotexaphyrin acetate, with a mixture of apical ligands, optionally heating the mixture, and isolating the MTD of Formula I containing a mixture of apical ligands. Alternatively, the reaction can be carried out in a biphasic fashion (for example, in a methylene chloride/water mixture).
A fifth aspect of this invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of an MTD of Formula I and at least one pharmaceutically acceptable excipient.
A sixth aspect of this invention relates to a method of using the MTDs of Formula I in the treatment of a disease or condition in a mammal that results from the presence of neoplastic tissue, which method comprises administering to a such a mammal a therapeutically effective amount of an MTD of Formula I, and optionally treating further with a chemotherapeutic compound, or preferably treating the area in proximity to the neoplastic tissue with a therapeutic energy means. Preferred therapeutic energies include photoirradiation, ionizing radiation, ultrasound, and neutron bombardment.
A seventh aspect of this invention relates to a method of using the MTDs of Formula I in the treatment of a disease or condition in a mammal that results from the presence of atherosclerosis, which method comprises administering to a such a mammal a therapeutically effective amount of an MTD of Formula I, and treating the area in proximity to the plaque caused by atherosclerosis with a therapeutic energy means. Preferred therapeutic energies include photoirradiation, ionizing radiation, ultrasound, and neutron bombardment.
An eighth aspect of this invention relates to a method of using the MTDs of Formula I in the treatment of a disease or condition in a mammal that results from areas of neovascularization, in particular age-related ocular degeneration, which method comprises administering to a such a mammal a therapeutically effective amount of an MTD of Formula I, and treating the area in proximity to the neovascularization with a therapeutic energy means. Preferred therapeutic energies include photoirradiation, ionizing radiation, ultrasound, and neutron bombardment.
This invention provides novel metallotexaphyrin derivatives (MTDs) having a wide range of physicochemical and biological properties, and methods of making them. In particular, the invention provides a method of exchanging the existing apical ligands of a metallotexaphyrin with one or more different apical ligands. The apical ligand exchange modifies the properties of the metallotexaphyrin by altering, for example, its solubility, solution pH, partition coefficient, or other physicochemical properties. Changing the pharmacokinetics and/or the biodistribution of the complex in this fashion may result in, for example, better clearance and/or selective uptake in various tissues, such as tumor tissue, or atheromatous plaque.
For example, greater solubility of the MTD when placed in a physiologically compatible buffer can be expected to give greater serum concentration that can be obtained in vivo. This is useful, for example, in delivering the MTD directly to the area of plaque by intra-arterial injection, in which case higher uptake can be achieved. Additionally, higher solubility leads to lower aggregation effects, which provides lower in-vivo toxicity.
In particular, gluconate or glucoronate apical ligands render the MTDs very soluble, and are consequently useful for indications that call for higher plasma concentrations of the MTD. The higher solubility of such compounds, as noted above, provides greater potential for tumor uptake of the compounds of the invention. Alternatively, cholate or deoxycholate ligands decrease the compound""s solubility and impart hydrophobicity. Hydrophobic compounds, when enclosed in a lipid vacuole, are useful for alternative delivery routes such as oral and topical administration. Additionally, by changing to amphiphilic apical ligands such as PEG acids, the MTDs of the invention can be made soluble in a wide variety of solvents.
The existing apical ligands of a metallotexaphyrin can be exchanged for a wide range of different apical ligands, including mono or polyanionic ligands, such as carboxylates of sugar derivatives and cholesterol derivatives, PEG acids, organic acids, organosulfates, organophosphates, or phosphates or other inorganic ligands.
It should be noted that metallomacrocycles other than metallotexaphyrins can be modified in the same manner as summarized above. That is, metallomacrocycle derivatives can be prepared from metallomacrocycles in a manner similar to those disclosed herein. Examples of macrocycles from which metallomacrocyclee derivative can be made are porphyrins, porphyrin isomers, porphyrin-like macrocycles, benzoporphyrins, alaskaphyrins, sapphyrins, rubyrins, porphycenes, chlorins, benzochlorins, and purpurins.
Definitions and General Parameters
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
The term xe2x80x9calkylxe2x80x9d refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to
1) an alkyl group as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SOxe2x80x94alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl; or
2) an alkyl group as defined above that is interrupted by 1-20 atoms independently chosen from oxygen, sulfur and NRaxe2x80x94, where Ra is chosen from hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic; or
3) an alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above.
One preferred alkyl substituent is hydroxy, exemplified by hydroxyalkyl groups, such as 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, and the like; dihydroxyalkyl groups (glycols), such as 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 2,4-dihydroxybutyl, and the like; and those compounds known as polyethylene glycols, polypropylene glycols and polybutylene glycols, and the like.
The term xe2x80x9calkylenexe2x80x9d refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms. This term is exemplified by groups such as methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), the propylene isomers (e.g., xe2x80x94CH2CH2CH2xe2x80x94and xe2x80x94CH(CH3)CH2xe2x80x94) and the like.
The term xe2x80x9csubstituted alkylenexe2x80x9d refers to:
(1) an alkylene group as defined above having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, thioaryloxy, heteroaryl, heteroaryloxy, thioheteroaryloxy, heterocyclic, heterocyclooxy, thioheterocyclooxy, nitro, and xe2x80x94NRaRb, wherein Ra and Rb may be the same or different and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. Additionally, such substituted alkylene groups include those where two substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group; or
(2) an alkylene group as defined above that is interrupted by 1-20 atoms independently chosen from oxygen, sulfur and NR1xe2x80x94, where Ra is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or
(3) an alkylene group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above.
Examples of substituted alkylenes are chloromethylene (xe2x80x94CH(Cl)xe2x80x94), aminoethylene (xe2x80x94CH(NH2)CH2xe2x80x94), methylaminoethylene ((xe2x80x94CH(NHMe)CH2xe2x80x94), 2-carboxypropylene isomers (xe2x80x94CH2CH(CO2H)CH2xe2x80x94), ethoxyethyl (xe2x80x94CH2CH2Oxe2x80x94CH2CH2xe2x80x94), ethylmethylaminoethyl (xe2x80x94CH2CH2N(CH3)CH2CH2xe2x80x94), 1-ethoxy-2-(2-ethoxyxe2x80x94ethoxy)ethane (xe2x80x94CH2CH2Oxe2x80x94CH2CH2xe2x80x94OCH2CH2xe2x80x94OCH2CH2xe2x80x94), and the like.
The term xe2x80x9calkarylxe2x80x9d refers to the groups-optionally substituted alkylene-optionally substituted aryl, where alkylene, substituted alkylene, aryl and substituted aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to the groups alkyl-Oxe2x80x94, alkenyl-Oxe2x80x94, cycloalkyl-Oxe2x80x94, cycloalkenyl-Oxe2x80x94, and alkynyl-Oxe2x80x94, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferred alkoxy groups are alkyl-Oxe2x80x94and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
The term xe2x80x9csubstituted alkoxyxe2x80x9d refers to the groups substituted alkyl-Oxe2x80x94, substituted alkenyl-Oxe2x80x94, substituted cycloalkyl-Oxe2x80x94, substituted cycloalkenyl-Oxe2x80x94, and substituted alkynyl-Oxe2x80x94where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein. One preferred substituted alkoxy group is substituted alkyl-O, and includes groups such as xe2x80x94OCH2CH2OCH3, PEG groups such as xe2x80x94O(CH2CH2O)xCH3, where x is an integer of 2-20, preferably 2-10, and more preferably 2-5. Another preferred substituted alkoxy group is xe2x80x94Oxe2x80x94CH2xe2x80x94(CH2)yxe2x80x94OH, where y is an integer of 1-10, preferably 1-4.
The term xe2x80x9calkylalkoxyxe2x80x9d refers to the groups -alkylene-Oxe2x80x94alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way of example, methylenemethoxy (xe2x80x94CH2OCH3), ethylenemethoxy (xe2x80x94CH2CH2OCH3), n-propylene-iso-propoxy (xe2x80x94CH2CH2CH2OCH(CH3)2), methylene-t-butoxy (xe2x80x94CH2xe2x80x94Oxe2x80x94C(CH3)3) and the like.
The term xe2x80x9calkylthioalkoxyxe2x80x9d refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, by way of example, methylenethiomethoxy (xe2x80x94CH2SCH3), ethylenethiomethoxy (xe2x80x94CH2CH2SCH3), n-propylene-iso-thiopropoxy (xe2x80x94CH2CH2CH2SCH(CH3)2), methylene-t-thiobutoxy (xe2x80x94CH2SC(CH3)3) and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. Preferred alkenyl groups include ethenyl (xe2x80x94CHxe2x95x90CH2), 1-propylene (xe2x80x94CH2CHxe2x95x90CH2), isopropylene (xe2x80x94C(CH3)xe2x95x90CH2), and the like.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9calkenylenexe2x80x9d refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. This term is exemplified by groups such as ethenylene (xe2x80x94CHxe2x95x90CHxe2x80x94), the propenylene isomers (e.g., xe2x80x94CH2CHxe2x95x90CHxe2x80x94and xe2x80x94C(CH3)xe2x95x90CHxe2x80x94) and the like.
The term xe2x80x9csubstituted alkenylenexe2x80x9d refers to an alkenylene group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl. Additionally, such substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group.
The term xe2x80x9calkynylxe2x80x9d refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl, (xe2x80x94Cxe2x89xa1CH), propargyl (or propynyl, xe2x80x94Cxe2x89xa1CCH3), and the like.
The term xe2x80x9csubstituted alkynylxe2x80x9d refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9calkynylenexe2x80x9d refers to a diradical of an unsaturated hydrocarbon preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynylene groups include ethynylene (xe2x80x94Cxe2x89xa1Cxe2x80x94), propargylene (xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94) and the like.
The term xe2x80x9csubstituted alkynylenexe2x80x9d refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9cacylxe2x80x9d refers to the groups HC(O)xe2x80x94, alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, cycloalkyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, alkenyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, cycloalkenyl-C(O)xe2x80x94, substituted cycloalkenyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94and heterocyclic-C(O)xe2x80x94 where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9cacylaminoxe2x80x9d or xe2x80x9caminocarbonylxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9caminoacylxe2x80x9d refers to the group xe2x80x94NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9caminoacyloxyxe2x80x9d or xe2x80x9calkoxycarbonylaminoxe2x80x9d refers to the group xe2x80x94NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9cacyloxyxe2x80x9d refers to the groups alkyl-C(O)Oxe2x80x94, substituted alkyl-C(O)Oxe2x80x94, cycloalkyl-C(O)Oxe2x80x94, substituted cycloalkyl-C(O)Oxe2x80x94, aryl-C(O)Oxe2x80x94, heteroaryl-C(O)Oxe2x80x94, and heterocyclic-C(O)Oxe2x80x94 wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term xe2x80x9carylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl and trihalomethyl.
The term xe2x80x9caryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
The term xe2x80x9carylenexe2x80x9d refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.
The term xe2x80x9caminoxe2x80x9d refers to the group xe2x80x94NH2.
The term xe2x80x9csubstituted amino refers to the group xe2x80x94NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that both R""s are not hydrogen.
The term xe2x80x9ccarboxyalkylxe2x80x9d or xe2x80x9calkoxycarbonylxe2x80x9d refers to the groups xe2x80x9cxe2x80x94C(O)O-alkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-substituted alkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)Oxe2x80x94cycloalkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-substituted cycloalkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-alkenylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-substituted alkenylxe2x80x9d, xe2x80x9cxe2x80x94C(O)Oxe2x80x94alkynylxe2x80x9d and xe2x80x9cxe2x80x94C(O)O-substituted alkynylxe2x80x9d where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl are as defined herein.
The term xe2x80x9ccycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
The term xe2x80x9csubstituted cycloalkylxe2x80x9d refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9ccycloalkylenexe2x80x9d refers to the diradical derived from cycloalkyl as defined above and is exemplified by 1,1-cyclopropylene, 1,2-cyclobutylene, 1,4-cyclohexylene and the like.
The term xe2x80x9csubstituted cycloalkylenexe2x80x9d refers to the diradical derived from substituted cycloalkyl as defined above.
The term xe2x80x9ccycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
The term xe2x80x9ccycloalkenylenexe2x80x9d refers to the diradical derived from cycloalkenyl as defined above and is exemplified by 1,2-cyclobut-1-enylene, 1,4-cyclohex-2-enylene and the like.
The term xe2x80x9csubstituted cycloalkenylxe2x80x9d refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9csubstituted cycloalkenylenexe2x80x9d refers to the diradical derived from substituted cycloalkenyl as defined above.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic group comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
The term xe2x80x9cheteroaryloxyxe2x80x9d refers to the group heteroaryl-Oxe2x80x94.
The term xe2x80x9cheteroarylenexe2x80x9d refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl and the like.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a monoradical saturated or unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, and the like.
Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles.
The term xe2x80x9cheterocyclooxyxe2x80x9d refers to the group heterocyclic-Oxe2x80x94.
The term xe2x80x9cthioheterocyclooxyxe2x80x9d refers to the group heterocyclic-SOxe2x80x94.
The term xe2x80x9cheterocyclenexe2x80x9d refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-morpholino, 2,5-morpholino and the like.
The term xe2x80x9coxyacylaminoxe2x80x9d or xe2x80x9caminocarbonyloxyxe2x80x9d refers to the group xe2x80x94OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9cspiro-attached cycloalkyl groupxe2x80x9d refers to a cycloalkyl group attached to another ring via one carbon atom common to both rings.
The term xe2x80x9cthiolxe2x80x9d refers to the group xe2x80x94SH.
The term xe2x80x9cthioalkoxyxe2x80x9d refers to the group xe2x80x94SO-alkyl.
The term xe2x80x9csubstituted thioalkoxyxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
The term xe2x80x9cthioaryloxyxe2x80x9d refers to the group arylxe2x80x94Sxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
The term xe2x80x9cthioheteroaryloxyxe2x80x9d refers to the group heteroaryl-Sxe2x80x94 wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
The term xe2x80x9ccarboxyamidesxe2x80x9d include primary carboxyamides (CONH2), secondary carboxyamides (CONHRxe2x80x2) and tertiary carboxyamides (CONRxe2x80x2Rxe2x80x3), where Rxe2x80x2 and Rxe2x80x3 are the same or different substituent groups chosen from alkyl, alkenyl, alkynyl, alkoxy, aryl, a heterocyclic group, a functional group as defined herein, and the like, which themselves may be substituted or unsubstituted.
xe2x80x9cCarboxyamidealkylxe2x80x9d means a carboxyamide as defined above attached to an optionally substituted alkylene group as defined above.
The term xe2x80x9csaccharidexe2x80x9d includes oxidized, reduced or substituted saccharides, including hexoses such as D-glucose, D-mannose or D-galactose; pentoses such as D-ribose or D-arabinose; ketoses such as D-ribulose or D-fructose; disaccharides such as sucrose, lactose, or maltose; derivatives such as acetals, amines, and phosphorylated sugars; oligosaccharides; as well as open chain forms of sugars, and the like. Examples of amine-derivatized sugars are galactosamine, glucosamine, and sialic acid.
The term xe2x80x9csite-directing moleculexe2x80x9d refers to a molecule having an affinity for a biological receptor or for a nucleic acid sequence. Exemplary site-directing molecules useful herein include, but are not limited to, polydeoxyribonucleotides, oligodeoxyribonucleotides, polyribonucleotide analogs, oligoribonucleotide analogs, polyamides including peptides having affinity for a biological receptor and proteins such as antibodies, steroids and steroid derivatives, hormones such as estradiol or histamine, hormone mimics such as morphine, and further macrocycles such as sapphyrins and rubyrins. The oligonucleotides may be derivatized at the bases, the sugars, the ends of the chains, or at the phosphate groups of the backbone to promote in vivo stability. Modifications of the phosphate groups are preferred in one embodiment since phosphate linkages are sensitive to nuclease activity. Presently preferred derivatives are the methylphosphonates, phosphotriesters, phosphorothioates, and phosphoramidates. Additionally, the phosphate linkages may be completely substituted with non-phosphate linkages such as amide linkages. Appendages to the ends of the oligonucleotide chains also provide exonuclease resistance. Sugar modifications may include groups, such as halo, alkyl, alkenyl or alkoxy groups, attached to an oxygen of a ribose moiety in a ribonucleotide. In a preferred embodiment, the group will be attached to the 2xe2x80x2 oxygen of the ribose. In particular, halogen moieties such as fluoro may be used. The alkoxy group may be methoxy, ethoxy or propoxy. The alkenyl group is preferably allyl. The alkyl group is preferably a methyl group and the methyl group is attached to the 2xe2x80x2 oxygen of the ribose. Other alkyl groups may be ethyl or propyl. It is understood that the terms xe2x80x9cnucleotidexe2x80x9d, xe2x80x9cpolynucleotidexe2x80x9d and xe2x80x9coligonucleotidexe2x80x9d, as used herein and in the appended claims, refer to both naturally-occurring and synthetic nucleotides, poly- and oligonucleotides and to analogs and derivatives thereof such as methylphosphonates, phosphotriesters, phosphorothioates, phosphoramidates and the like. Deoxyribonucleotides, deoxyribonucleotide analogs and ribonucleotide analogs are contemplated as site-directing molecules in the present invention. The term xe2x80x9ctexaphyrin-oligonucleotide conjugatexe2x80x9d means that an oligonucleotide is attached to the texaphyrin in a 5xe2x80x2 or a 3xe2x80x2 linkage, or in both types of linkages to allow the texaphyrin to be an internal residue in the conjugate. It can also refer to a texaphyrin that is linked to an internal base of the oligonucleotide. The oligonucleotide or other site-directing molecule may be attached either directly to the texaphyrin or to the texaphyrin via a linker or a couple of variable length.
The term xe2x80x9ccatalytic groupxe2x80x9d means a chemical functional group that assists catalysis by acting as a general acid, Bronsted acid, general base, Bronsted base, nucleophile, or any other means by which the activation barrier to reaction is lowered. Exemplary catalytic groups contemplated include, but are not limited to, imidazole; guanidine; substituted saccharides such as D-glucosamine, D-mannosamine, D-galactosamine, D-glucamine and the like; amino acids such as L-histidine and L-arginine; derivatives of amino acids such as histamine; polymers of amino acids such as poly-L-lysine, (LysAla), (LysLeuAla)n where n is from 1-30 or preferably 1-10 or more preferably 2-7 and the like; derivatives thereof; and metallotexaphyrin complexes.
A xe2x80x9cchemotherapeutic agentxe2x80x9d may be, but is not limited to, one of the following: an alkylating agent such as a nitrogen mustard, an ethyleneimine or a methylmelamine, an alkyl sulfonate, a nitrosourea, or a triazene; an antimetabolite such as a folic acid analog, a pyrimidine analog, or a purine analog; a natural product such as a vinca alkaloid, an epipodophyllotoxin, an antibiotic, an enzyme, taxane, or a biological response modifier; miscellaneous agents such as a platinum coordination complex, an anthracenedione, an anthracycline, a substituted urea, a methyl hydrazine derivative, or an adrenocortical suppressant; or a hormone or an antagonist such as an adrenocorticosteroid, a progestin, an estrogen, an antiestrogen, an androgen, an antiandrogen, or a gonadotropin-releasing hormone analog. Chemotherapeutic agents are used in the treatment of cancer and other neoplastic tissue. Preferably, the chemotherapeutic agent is a nitrogen mustard, an epipodophyllotoxin, an antibiotic, or a platinum coordination complex. A more preferred chemotherapeutic agent is bleomycin, doxorubicin, taxol, taxotere, etoposide, 4-OH cyclophosphamide, cisplatin, or platinum coordination complexes analogous to cisplatin. A presently preferred chemotherapeutic agent is doxorubicin, taxol, taxotere, cisplatin, or Pt complexes analogous to cisplatin. Various chemotherapeutic agents, their target diseases, and treatment protocols are presented in, for example, Goodman and Gilman""s The Pharmacological Basis of Therapeutics, Ninth Ed., Pergamon Press, Inc., 1990; and Remington: The Science and Practice of Pharmacy, Mack Publishing Co., Easton, Pa., 1995; both of which are incorporated by reference herein.
A site directing molecule, or a group having or catalytic or chemotherapeutic activity, identified above by the symbol Y, may be covalently coupled to any position on a metallotexaphyrin by a covalent bond or by a linker (identified above by the symbol X). The term xe2x80x9clinkerxe2x80x9d as used herein means a group that covalently connects Y to a metallotexaphyrin, and may be, for example, alkylene, alkenylene, alkynylene, arylene, ethers, PEG moieties, and the like, all of which may be optionally substituted. Examples of reactions to form a covalent link include reaction between an amine (on either the molecule Y or X) with a carboxylic acid (on the corresponding X or Y) to form an amide link. Similar reactions well known in the art are described in standard organic chemistry texts such as J. March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th Edition, (Wiley-Interscience (New York), 1992.
The term xe2x80x9cmacrocyclexe2x80x9d as used herein refers to a class of polypyrrole macrocycles that are capable of forming stable complexes with metals by incorporating a metal (as its cation) within a central binding cavity (core) of the macrocycle, and the anions associated with the metal cation are found above and below the core; these anions are known as apical ligands. This class of macrocycles includes porphyrins, the so-called xe2x80x9cexpanded porphyrinsxe2x80x9d, and similar structures. Specific examples are porphyrins, porphyrin isomers, porphyrin-like macrocycles, benzophyrins, texaphyrins, alaskaphyrins, sapphyrins, rubyrins, porphycenes, chlorins, benzochlorins, and purpurins.
The term xe2x80x9capical ligandxe2x80x9d refers to an anion that binds to the core metal of the MTD with de-localized electrostatic bonds. The number of apical ligands (n) is defined as an integer of 1-5. It should be noted that the apical ligands act to neutralize the charge on the metallotexaphyrin. Thus, typically n is 1 when M is a divalent cation, and n is 2 when M is a trivalent cation (because the core itself neutralizes one unit charge). However, if any of R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, and R12 is capable of forming an acid addition salt, for example a carboxylate or a phosphate, then n will decrease appropriately. It is also possible that the apical ligands could have two functionalities capable of forming an anion, for example a dicarboxylic acid, and such ligands are intended to be within the scope of the invention.
In general, any molecule containing a carboxylic acid or phosphate may be used as an apical ligand, for example biomolecules, including lipoproteins, estradiol and amino acids, carboxylates of sugar derivatives, such as gluconic acid or glucoronic acid, cholesterol derivatives such as cholic acid and deoxycholic acid, PEG acids, organophosphates, such as methylphosphonic acid and phenylphosphonic acid, and phosphoric acid or other inorganic acids, and the like, or sulfonic acid derivatives such as methanesulfonic acid, ethanesulfonic acid or xe2x80x9ccarboxylic acid derivativesxe2x80x9d, which term refers to compounds of the formula Rxe2x80x94CO2H, in which R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl, as defined above. Preferred are gluconic and glucuronic acid, and those carboxylic acid derivatives where R is optionally substituted alkyl, for example acids of 1-20 carbon atoms, such as formic acid, acetic acid, propionic acid, butyric acid, pentanoic acid, 3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, and the like. Also preferred are those carboxylic acid derivatives where R is aryl, in particular where R is optionally substituted phenyl, for example benzoic acid, salicylic acid, 3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelic acid, p-toluene-sulfonic acid, 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propanoic acid, and the like.
It should be noted that the term xe2x80x9capical ligandsxe2x80x9d as associated with metallotexaphyrins was employed in U.S. Pat. No. 4,935,498, in which the apical ligands were said to include pyridine and benzimidazole, and in U.S. Pat. No. 5,801,229, in which the apical ligands were said to include acetate, chloride, nitrate, hydroxy, water, and methanol. However, pyridine, benzimidazole, water, and methanol are not apical ligands as defined herein, since they are not anions associated with a metal cation; for the purpose of this application, such derivatives are referred to as xe2x80x9ccoordination complexes.xe2x80x9d
As to any of the above groups that contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
The term xe2x80x9ccompound of Formula Ixe2x80x9d is intended to encompass the metallotexaphyrins of the invention as disclosed, coordination complexes of the compounds of Formula I, and/or the pharmaceutically acceptable salts of such compounds.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to that amount of an MTD of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will provide an image for detection by any one of the imaging methods described herein. The specific dose will vary depending on the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.
xe2x80x9cTexaphyrinxe2x80x9d means an aromatic pentadentate macrocyclic expanded porphyrins, also described as an aromatic benzannulene containing both 18xcfx80- and 22xcfx80-electron delocalization pathways. Texaphyrins and water-soluble texaphyrins, method of preparation and various uses have been described in U.S. Pat. Nos. 4,935,498, 5,162,509, 5,252,720, 5,256,399, 5,272,142, 5,292,414, 5,369,101, 5,432,171, 5,439,570, 5,451,576, 5,457,183, 5,475,104, 5,504,205, 5,525,325, 5,559,207, 5,565,552, 5,567,687, 5,569,759, 5,580,543, 5,583,220, 5,587,371, 5,587,463, 5,591,422, 5,594,136, 5,595,726, 5,599,923, 5,599,928, 5,601,802, 5,607,924, 5,622,946, and 5,714,328; PCT publications WO 90/10633, 94/29316, 95/10307, 95/21845, 96/09315, 96/40253, 96/38461, 97/26915, 97/35617, 97/46262, and 98/07733; allowed U.S. patent applications Ser. Nos. 08/458,347, 08/591,318, and 08/914,272; and pending U.S. patent application Ser. Nos. 08/763,451, 08/903,099, 08/946,435, 08/975,090, 08/975,522, 08/988,336, and 08/975,526; each of which are herein incorporated by reference in their entirety.
Texaphyrins are illustrated as a compound of Formula I above. Two positions on the compound of Formula I are designated as R1, and two positions are designated as R4. This is because, in general, the disclosed methods of synthesis of texaphyrins leads to the same substituent at R1, and the same substituents at R4. However, it should be noted that methods of synthesis of texaphyrins in which these positions are the same or different are described in U.S. patent application Ser. No. 60/229,247, filed on Aug. 30, 2000, the complete disclosure of which is hereby incorporated by reference in its entirety.
xe2x80x9cSapphyrinsxe2x80x9d and water-soluble sapphyrins and methods of preparation have been described in U.S. Pat. Nos. 5,041,078; 5,120,411; 5,159,065; 5,302,714; 5,457,195; 5,530,123; 5,543,514; and 5,672,490; and in International Publn. WO 94/09003; all of which are incorporated herein by reference in its entirety.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
xe2x80x9cWater solublexe2x80x9d means soluble in an aqueous medium to about 1 mM or more.
As used herein, xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
The term xe2x80x9ctreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any treatment of a disease in a mammal, including:
(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or
(iii) relieving the disease, that is, causing the regression of clinical symptoms.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to salts which retain the biological effectiveness and properties of the MTDs of this invention and which are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
The naming and numbering of the MTDs of the present invention is illustrated with a representative compound texaphyrin of Formula I, AL is gluconate (Gluc), and the metal M is lutetium (Lu), depicted below as a compound of Formula IA: 
This compound can be named in a variety of ways (e.g. depending on the origination of the numbering). Examples of alternative names for this compound are:
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxy propyl)-16,17-bis[2-[2-(2 methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.13,6.18.11.014,19]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene bis gluconate; or Bis(gluconato-O)[9,10-diethyl-20,21-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4,15-dimethyl-8,11-imino-3,6,16,13-dinitrilo-1,18-benzodiazacyclooeicosine-5,14-dipropanolato-N1, N18, N23, N24, N25]lutetium; or
Lutetium texaphyrin bis-gluconate; or
Lu-Tex bis-gluconate; or
Lu-Tex digluconate.
For the purposes of this specification, the format (Metal)-Macrocycle-Apical Ligand (such as LuTex diacetate or LuTex bisacetate, or LuTex bis-gluconate) is preferred.
Synthetic Reaction Parameters
The terms xe2x80x9csolventxe2x80x9d, xe2x80x9cinert organic solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (xe2x80x9cTHFxe2x80x9d), dimethylformamide (xe2x80x9cDMFxe2x80x9d), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like]. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents.
The term xe2x80x9cq.s.xe2x80x9d means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure within a temperature range from 5xc2x0 C. to 100xc2x0 C. (preferably from 10xc2x0 C. to 50xc2x0 C.; most preferably at about xe2x80x9croomxe2x80x9d or xe2x80x9cambientxe2x80x9d temperature, e.g., about 20xc2x0 C.).
Further, unless otherwise specified, the reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about 5xc2x0 C. to about 100xc2x0 C. (preferably from about 10xc2x0 C. to about 50xc2x0 C.; most preferably about 20xc2x0 C.) over a period of about 1 to about 10 hours (preferably about 5 hours). Parameters given in the Examples are intended to be specific, not approximate.
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure, such as crystallization, distillation, filtration, extraction, column chromatography, solvent evaporation under reduced pressure; thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
Alternative syntheses of the compounds of Formula I are described below with reference to Reaction Schemes 1 and 2.
Reaction Scheme 1 illustrates a preferred synthesis of the compounds of Formula I. A texaphyrin with the desired apical ligand(s) (a compound of Formula I) is obtained by an exchange reaction between a metallotexaphyrin having displaceable apical ligands, preferably acetate, and an appropriately charged ion exchange resin. To this end, the desired apical ligand (AL)H is bound to an ion exchange resin, and the ion exchange resin complex thus obtained is reacted with the starting metallotexaphyrin having displaceable apical ligands. The product is separated and purified conventionally. 
in which T is a texaphyrin, M is a metal, (AL1) represents the apical ligand associated with the starting texaphyrin, (AL) represents the desired apical ligand that replaces (AL1), n is an integer of 1-5, and the ion exchange resin is a commercially available resin such as Ambersep(copyright) 900 (OH) anion exchange resin.
For example, starting with a compound in which T is the texaphyrin illustrated as the compound of Formula IA, as its bis acetate, and reacting with an ion exchange resin prepared with gluconic acid (i.e., (AL)H is gluconic acid), the product obtained is LuTex bis gluconate, a compound of Formula I.
Reaction Scheme 2 illustrates an alternative synthesis of the compounds of Formula I, utilizing an in-situ exchange of apical ligands. A metallotexaphyrin having one or more apical ligands, preferably acetate, is reacted with an excess of the desired apical ligand, optionally at raised temperatures. 
in which T is a texaphyrin, M is a metal, (AL1) represents the apical ligand associated with M of the starting texaphyrin, (AL) represents the desired apical ligand that replaces (AL1), and n is an integer of 1-5.
For example, starting with a compound in which T is the texaphyrin illustrated as the compound of Formula IA, as its bis acetate, and reacting with an excess of gluconic acid (i.e., (AL)H is gluconic acid), the product obtained is LuTex bis gluconate, a compound of Formula IA. The compound of Formula I is then separated from the mixture conventionally.
Reaction Scheme 3 shows the preparation of a mixture of compounds of Formula. 
in which T is a texaphyrin, M is a metal, (AL1) represents the apical ligand associated with M of the starting texaphyrin, (AL2) and (AL3) represent a mixture of desired apical ligands that replaces (AL1), and n is an integer of 1-5.
This reaction can be carried out as in Reaction Scheme I (using an ion exchange resin), or as shown in Reaction Scheme 2 (using a large excess of a mixture of the apical ligands). Alternatively, the reaction can be carried out in a biphasic mixture, for example in a methylene chloride/water mixture.
An alternative method of preparing the compounds of the invention is to first prepare a metal-apical ligand M(Al)n, where M, Al, and n are as defined above, and then reacting this metal complex with a texaphyrin, and an oxidizing agent, for example oxygen, to give a metallated texaphyrin of Formula I.
Substituting a metallomacrocycle, as defined above, for a metallotexaphyrin in the above reaction schemes and carrying out the reaction in a similar manner provides metallomacrocycle derivatives having different apical ligands.
The anion exchange resin is commercially available, e.g., from Rohm and Haas. The desired apical ligands, such as gluconic acid, are likewise commercially available or may be readily prepared by those skilled in the art using commonly employed synthetic methodology.
Preferred are the compounds of Formula I in which M is a divalent or trivalent metal, R1 is hydroxyalkyl (in which alkyl preferably has 1-10 carbon atoms), R2, R3 and R4 are alkyl (preferably of 1-6 carbon atoms), R7 and R8 are substituted alkoxy (in which alkoxy preferably has 1-20 carbon atoms), and n is 1-4. R5, R6, R9, R10, R11 and R12 are hydrogen or alkyl of 1-6 carbon atoms.
More preferred are the compounds of Formula I where M is lutetium or gadolinium, R1 is 2-hyrdoxyethyl or 3-hydroxypropyl, R2, R3 and R4 are methyl or ethyl, R7 and R8 are 2-[2-(2-methoxyethoxy)ethoxy]ethoxy], and n is 2. R5, R6, R9, R10, R11, and R12 are preferably hydrogen or methyl.
Most preferred are the following compounds:
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1.3,6.18,11.014,19]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene bis gluconate;
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy) ethoxy]ethoxy]pentaazapentacyclo[20.2.1.13,6.18,11.014,19]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene bis glucoronate;
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.13,6.18,11.014,19]-heptacosa-1,3,5,7,9,11 (27),12,14,16,18,20,22(25), 23-tridecaene bis formate;
The lutetium (III complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.13,6.18,11.014,19]-heptacosa-1,3,5,7,9,1 (27),12,14,16,18,20,22(25), 23-tridecaene bis benzoate;
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.13,6.18,11.014,19]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene bis methylvalerate;
The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1 3,6..18,11.014,19]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis deoxycholate;
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy) ethoxy]ethoxy]pentaazapentacyclo[20.2.1.13,6.18,11.014,19]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis 3,6,9-trioxodecanoate;
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy) ethoxy]ethoxy]pentaazapentacyclo[20.2.1.13,6.8,110. 14,19]-heptacosa-1,3,5,7,9,1 (27),12,14,16,18,20,22(25), 23-tridecaene bis 3,6-dioxoheptanoate;
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.13,6.181,1.014,19]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene methylphosphonate;
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy) ethoxy]ethoxy]pentaazapentacyclo[20.2.1.13,6..18,11.014,19]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene phenylphosphonate; and
The lutetium (III) complex of: 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy) ethoxy] ethoxy]pentaazapentacyclo[20.2.1.1 3,6.18,11.014,19]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene bis-cholate.
The MTDs of the present invention can be prepared according to the following last steps:
1. Contacting a metellotexaphyrin of the formula (Txe2x88x92M)n+-(AL1)n with an Ion Exchange Resin-(AL) complex, to give (Txe2x88x92M)n+-(AL)n, a product of Formula I; in which T is a texaphyrin, M is a divalent or trivalent metal, (AL1) represents the apical ligand associated with M of the starting texaphyrin, (AL) represents the apical ligand that replaces (AL1), n is 1 or 2, and the ion exchange resin is a commercially available resin such as Ambersep(copyright) 900 (OH) anion exchange resin.
2. Contacting a metallotexaphyrin of the formula (Txe2x88x92M)n+-(AL1)n with an excess of (AL)H ligand, to give (Txe2x88x92M)n+-(AL)n, a product of Formula I.
3. Contacting a metallotexaphyrin of the formula (Txe2x88x92M)n+-(AL1)n with a mixture of (AL2)H and (AL3 )H ligands, to give a mixture of (Txe2x88x92M)n+-(AL2)n, (Txe2x88x92M)n+-(AL3)n, and (Txe2x88x92M)n+-(AL2)(AL3), a mixture of products of Formula I.
4. Contacting a metallotexaphyrin of the formula (Txe2x88x92M)n+-(AL1)n with a reverse phase chromatography absorption column, contacting the column with a salt of the apical ligand (AL), and eluting with a suitable solvent, for example methanol, to give (Txe2x88x92M)n+-(AL)n a product of Formula I.
General Utility
The MTDs of the present invention are effective in the treatment of conditions known to respond to metallotexaphyrin therapy, including diseases characterized by neoplastic tissue, (e.g. the cancers sarcoma, lymphoma, leukemia, carcinoma, brain metastases, glioma, glioblastoma, cancer of the prostate, melanoma, and the like), cardiovascular diseases (e.g., atherosclerosis, intimal hyperplasia and restenosis) and other activated macrophage-related disorders including autoimmune diseases (e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki""s disease, psoriasis, Type I diabetes, pemphigus vulgaris, multiple sclerosis), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener""s granulomatosus), inflammatory diseases (e.g., inflammatory lung diseases such as interstitial pneumonitis and asthma, inflammatory bowel disease such as Crohn""s disease, and inflammatory arthritis), in transplant rejection (e.g., in heart/lung transplants) and in ophthalmic diseases that result from undesired neovascularization, in particular age-related macular degeneration.
Testing
Activity testing is conducted as described in those patents and patent applications incorporated by reference above, and in the following references, and by modifications thereof. The MTDs of Formula I have been shown to have various in vitro and in vivo activity. See e.g. Young et al., Methods for Cancer Chemosensitization, and U.S. Pat. No. 5,776,925.
Determination of the various physicochemical characteristics of each MTD can be performed, and are apparent to one skilled in the art and are detailed in, for example, Pharmaceutical Dosage Forms: Parenteral Medications vol. 1, Marcel Dekker Inc., New York, N.Y., 2nd Edition, 1992. The generally accepted tests performed to determine the MTD""s characteristics include, for example: determination of solubility, the partition coefficient, the extinction coefficient, and the solution pH of the MTD.
Pharmaceutical Compositions
The MTDs of Formula I are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the MTDs of Formula I, or a pharmaceutically acceptable salt AND/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The MTDs may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington""s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985) and xe2x80x9cModern Pharmaceuticsxe2x80x9d, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker and C. T. Rhodes, Eds.).
Administration
The MTDs of Formula I may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference above, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer, with parenteral and intra-arterial administration being preferred, and intra-arterial being more preferred.
One preferred mode for administration is parental, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
It has been discovered that texaphyrins have a tendency to aggregate in aqueous solution, which potentially decreases their solubility. Aggregation (self-association) of polypyrrolic macrocyclic compounds, including porphyrins, sapphyrins, texaphyrins, and the like, is a common phenomenon in water solution as the result of strong intermolecular van der Waals attractions between these flat aromatic systems. Aggregation may significantly alter the photochemical characteristics of the macrocycles in solution, which is shown by large spectral changes, decrease in extinction coefficient, etc.
It has been found that addition of a carbohydrate, saccharide, polysaccharide, or polyuronide to the formulation decreases the tendency of the texaphyrin to aggregate, thus increasing the solubility of the texaphyrin in aqueous media. Preferred anti-aggregation agents are sugars, in particular mannitol, dextrose or glucose, preferably mannitol of about 2-8% concentration, more preferably about 5% concentration. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure.
Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. These particular aqueous solutions are especially suitable for intra-arterial, intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media that can be employed will be known to those skilled in the art in light of the present disclosure.
Sterile injectable solutions are prepared by incorporating the active MTDs in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
MTDs of Formula I may be impregnated into a stent by diffusion, for example, or coated onto the stent such as in a gel form, for example, using procedures known to one of skill in the art in light of the present disclosure.
Oral administration is another route for administration of the MTDs of this invention. Preferred is oral administration via capsule or enteric coated tablets, or the like, which prevent degradation of the MTDs of the invention in the stomach. In making the pharmaceutical compositions that include at least one MTD of Formula I, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, in can be a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902514; and 5,616,345. Another preferred formulation for use in the methods of the present invention employs transdermal delivery devices (xe2x80x9cpatchesxe2x80x9d). Such transdermal patches may be used to provide continuous or discontinuous infusion of the MTDs of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
The compositions are preferably formulated in a unit dosage form. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The active MTD is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 10 mg to 2 g of an MTD of Formula I, and for parenteral administration, preferably from 10 to 700 mg of an MTD of Formula I, preferably about 350 mg. It will be understood, however, that the amount of the MTD actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of an MTD of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
The MTDs disclosed herein can be used both diagnostically (e.g. magnetic resonance or fluorescence imaging to detect the presence of a disease) and therapeutically (to treat that disease).
Activation Means
The compounds of the invention to be used will be administered in a therapeutically effective amount, employing a method of administration and a pharmaceutical formulation as discussed above, and optionally a means of activation of the compound (through a therapeutic energy or agent) as is known in the art. The therapeutic energy or agent to be used includes photodynamic therapy, radiation sensitization, chemotherapy, sonodynamic therapy, and neutron bombardment. The specific dose will vary depending on the particular compound of Formula I chosen, the dosing regimen to be followed, and the particular therapeutic energy or agent with which it is administered. Such dose can be determined by methods known in the art or as described herein.
Dosages: The specific dose will vary depending on the particular compound of Formula I chosen, the dosing regimen to be followed, and the particular therapeutic energy or agent with which it is administered, employing dosages within the range of about 0.01 mg/kg/treatment up to about 100 mg/kg/treatment, preferably about 0.1 mg/kg/treatment to about 50 mg/kg/treatment. It will be appreciated by one skilled in the art, however, that there are specific differences in the most effective dosimetry depending on the apical ligands chosen, because of the wide range of properties available, such as solubilities, lipophilicity properties, lower toxicity, and improved stability.
Administration for Photodynamic Therapy
By way of example, lutetium texaphyrin may be administered in solution, optionally in 5% mannitol USP. Dosages of about 1.0-2.0 mg/kg to about 4.0-7.0 mg/kg, preferably 3.0 mg/kg, are employed, although in some cases a maximum tolerated dose may be higher, for example about 5 mg/kg. The texaphyrin is administered by intravenous injection, followed by a waiting period of from as short a time as several minutes or about 3 hours to as long as about 72 or 96 hours (depending on the treatment being effected) to facilitate intracellular uptake and clearance from the plasma and extracellular matrix prior to the administration of photoirradiation.
Dose levels for certain uses may range from about 0.05 mg/kg to about 20 mg/kg administered in single or multiple doses (e.g. before each fraction of radiation). The lower dosage range would be preferred for intra-arterial injection or for impregnated stents.
The co-administration of a sedative (e.g., benzodiazapenes) and narcotics/analgesics are sometimes recommended prior to light treatment along with topical administration of a local anesthetic, for example Emla cream (lidocaine, 2.5% and prilocaine, 2.5%) under an occlusive dressing. Other intradermal, subcutaneous and topical anesthetics may also be employed as necessary to reduce discomfort. Subsequent treatments can be provided after approximately 21 days.
The optimum length of time following administration of an MTD of Formula I until light treatment can vary depending on the mode of administration, the form of administration, and the type of target tissue. Typically, the MTD of Formula I persists for a period of minutes to hours, depending on the compound of Formula I, the formulation, the dose, the infusion rate, as well as the type of tissue and tissue size.
When employing photodynamic therapy, a target area is treated with light at about 732xc2x116.5 nm (full width at half max) delivered by an LED device or an equivalent light source (e.g., a Quantum Device Qbeam(trademark) BMEDXM-728 Solid State Lighting System, which operates at 728 nm) at an intensity of 5-150 mW/cm2 for a total light dose of 0.5-600 J/cm2, or a solid state diode laser, such as the DioMed 6 WW, 15 W laser).
After the photosensitizing MTD of Formula I has been administered, the tissue being treated is photoirradiated at a wavelength similar to the absorbance of the compound of Formula I, usually either about 400-500 nm or about 700-800 nm, more preferably about 450-500 nm or about 710-760 nm, or most preferably about 450-500 nm or about 725-740 nm. The light source may be a laser, a light-emitting diode, or filtered light from, for example, a xenon lamp; and the light may be administered topically, endoscopically, or interstitially (via, e.g., a fiber optic probe), or intraarterially. Preferably, the light is administered using a slit-lamp delivery system. The fluence and irradiance during the photoirradiating treatment can vary depending on type of tissue, depth of target tissue, and the amount of overlying fluid or blood. For example, a total light energy of about 100 J/cm2 can be delivered at a power of 200 mW to 250 mW, depending upon the target tissue.
Administration for Chemosensitization
MTDs of Formula I may be administered before, at the same time, or after administration of one or more chemotherapeutic drugs. The MTD of Formula I may be administered as a single dose, or it may be administered as two or more doses separated by an interval of time. The MTD of Formula I may be administered concurrently with, or from about one minute to about 12 hours following, administration of a chemotherapeutic drug, preferably from about 5 min to about 5 hr, more preferably about 4 to 5 hr. The dosing protocol may be repeated, from one to three times, for example. A time frame that has been successful in vivo is administration of an MTD of Formula I about 5 min and about 5 hr after administration of a chemotherapeutic agent, with the protocol being performed once per week for three weeks. Administration may be intra-arterial injection, intravenous, intraperitoneal, intramuscular, subcutaneous, oral, topical, or via a device such as a stent, for example, with parenteral and intra-arterial administration being preferred, and intra-arterial being more preferred.
Administering an MTD of Formula I and a chemotherapeutic drug to the subject may be prior to, concurrent with, or following vascular intervention. The method may begin at a time roughly accompanying a vascular intervention, such as an angioplastic procedure, for example. Multiple or single treatments prior to, at the time of, or subsequent to the procedure may be used. xe2x80x9cRoughly accompanying a vascular interventionxe2x80x9d refers to a time period within the ambit of the effects of the vascular intervention. Typically, an initial dose of an MTD of Formula I and chemotherapeutic drug will be within 6-12 hours of the vascular intervention, preferably within 6 hours thereafter. Follow-up dosages may be made at weekly, biweekly, or monthly intervals. Design of particular protocols depends on the individual subject, the condition of the subject, the design of dosage levels, and the judgment of the attending practitioner.
Administration for Radiation Sensitization
MTDs of Formula I where the metal is gadolinium are typically administered in a solution containing 2 mM optionally in 5% mannitol USP/water (sterile and non-pyrogenic solution). Dosages of 0.1 mg/kg up to as high as about 29.0 mg/kg have been delivered, preferably about 3.0 to about 15.0 mg/kg (for volume of about 90 to 450 mL) may be employed, optionally with pre-medication using anti-emetics when dosing above about 6.0 mg/kg. The MTD is administered via intravenous injection over about a 5 to 10 minute period, followed by a waiting period of about 2 to 5 hours to facilitate intracellular uptake and clearance from the plasma and extracellular matrix prior to the administration of radiation.
When employing whole brain radiation therapy, a course of 30 Gy in ten (10) fractions of radiation may be administered over consecutive days excluding weekends and holidays. In the treatment of brain metastases, whole brain megavolt radiation therapy is delivered with 60 Co teletherapy or a xe2x89xa74 MV linear accelerator with isocenter distances of at least 80 cm, using isocentric techniques, opposed lateral fields and exclusion of the eyes. A minimum dose rate at the midplane in the brain on the central axis is about 0.5 Gy/minute.
MTDs of Formula I used as radiation sensitizers may be administered before, or at the same time as, or after administration of the ionizing radiation. The MTD of Formula I may be administered as a single dose, as an infusion, or it may be administered as two or more doses separated by an interval of time. Where the MTD of Formula I is administered as two or more doses, the time interval between the MTD of Formula I administrations may be from about one minute to a number of days, preferably from about 5 min to about 1 day, more preferably about 4 to 5 hr. The dosing protocol may be repeated, from one to ten or more times, for example. Dose levels for radiation sensitization may range from about 0.05 mg/kg to about 20 mg/kg administered in single or multiple doses (e.g. before each fraction of radiation). The lower dosage range would be preferred for intra-arterial injection or for impregnated stents.
Administration may be intra-arterial injection, intravenous, intraperitoneal, intramuscular, subcutaneous, oral, topical, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer, with intravenous and intra-arterial administration being preferred, and intra-arterial being more preferred. In one aspect of the invention, a patient having restenosis or at risk for restenosis is administered a dose of MTD of Formula I at intervals with each dose of radiation.
Administering a MTD of Formula I to the subject may be prior to, concurrent with, or following vascular intervention, and the intervention is followed by radiation. The method may begin prior to, such as about 24-48 hours prior to, or at a time roughly accompanying vascular intervention, for example. Multiple or single treatments prior to, at the time of, or subsequent to the procedure may be used. xe2x80x9cRoughly accompanying the vascular interventionxe2x80x9d refers to a time period within the ambit of the effects of the vascular intervention. Typically, an initial dose of MTD of Formula I and radiation will be within 1-24 hours of the vascular intervention, preferably within about 5-24 hours thereafter. Follow-up dosages may be made at weekly, biweekly, or monthly intervals. Design of particular protocols depends on the individual subject, the condition of the subject, the design of dosage levels, and the judgment of the attending practitioner.
Administration for Sonodynamic Therapy:
The use of texaphyrins in sonodynamic therapy is described in U.S. patent application Ser. No. 09/111,148, which is incorporated herein by reference. Texaphyrin is administered before administration of the ultrasound. The texaphyrin may be administered as a single dose, or it may be administered as two or more doses separated by an interval of time. Parenteral administration is typical, including by intravenous and interarterial injection. Other common routes of administration can also be employed.
Ultrasound is generated by a focused array transducer driven by a power amplifier. The transducer can vary in diameter and spherical curvature to allow for variation of the focus of the ultrasonic output. Commercially available therapeutic ultrasound devices may be employed in the practice of the invention. The duration and wave frequency, including the type of wave employed may vary, and the preferred duration of treatment will vary from case to case within the judgment of the treating physician. Both progressive wave mode patterns and standing wave patterns have been successful in producing cavitation of diseased tissue. When using progressive waves, the second harmonic can advantageously be superimposed onto the fundamental wave.
Preferred types of ultrasound employed in the present invention are ultrasound of low intensity, non-thermal ultrasound, i.e., ultrasound generated within the wavelengths of about 0.1 MHz and 5.0 MHz and at intensities between about 3.0 and 5.0 W/cm2.
Administration for Neutron Capture Therapy
The use of metallotexaphyrins in neutron capture therapy is described in U.S. patent application Ser. No. 60/229,366, entitled xe2x80x9cAgents for Neutron Capture Therapyxe2x80x9d, filed on Aug. 30, 2000, which is incorporated herein in its entirety by reference. The metallotexaphyrin is administered before administration of the neutron beam. It may be administered as a single dose, or it may be administered as two or more doses separated by an interval of time. Parenteral administration is typical, including by intravenous and interarterial injection. Other common routes of administration can also be employed.
Further Administration Protocols
MTDs of Formula I and a suitable co-therapeutic agent can also be administered in the context of other medical procedures. For example, in allograft transplantation administration may be accomplished by perfusion of the graft prior to implantation. Following a brief period for uptake, e.g., by macrophages, the remaining MTD of Formula I is rinsed from the graft followed by application of the co-therapeutic agent. Administration to selectively treat diseases characterized by circulating macrophages may be accomplished by extracorporeal contact, filtration of non-absorbed MTD of Formula I employing a lipophilic filter, followed by application of the co-therapeutic agent.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.